Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Department of Microbiology and Plant Pathology, Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, USA.
mBio. 2021 Aug 31;12(4):e0215321. doi: 10.1128/mBio.02153-21.
The prevalence of Aspergillus fumigatus colonization in individuals with cystic fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management of A. fumigatus in CF individuals, due largely to uncertainty surrounding A. fumigatus CF pathogenesis and virulence mechanisms. To address this gap in knowledge, a longitudinal series of A. fumigatus isolates from an individual with CF were collected over 4.5 years. Isolate genotypes were defined with whole-genome sequencing that revealed both transitory and persistent A. fumigatus in the lung. Persistent lineage isolates grew most readily in a low-oxygen culture environment, and conidia were more sensitive to oxidative stress-inducing conditions than those from nonpersistent isolates. Closely related persistent isolates harbored a unique allele of the high-osmolarity glycerol (HOG) pathway mitogen-activated protein kinase kinase, Pbs2 (). Data suggest this novel allele arose and is necessary for the fungal response to osmotic stress in a low-oxygen environment through hyperactivation of the HOG (SakA) signaling pathway. Hyperactivation of the HOG pathway through comes at the cost of decreased conidial stress resistance in the presence of atmospheric oxygen levels. These novel findings shed light on pathoadaptive mechanisms of A. fumigatus in CF, lay the foundation for identifying persistent A. fumigatus isolates that may require antifungal therapy, and highlight considerations for successful culture of persistent Aspergillus CF isolates. Aspergillus fumigatus infection causes a spectrum of clinical manifestations. For individuals with cystic fibrosis (CF), allergic bronchopulmonary aspergillosis (ABPA) is an established complication, but there is a growing appreciation for A. fumigatus airway persistence in CF disease progression. There currently is little consensus for clinical management of A. fumigatus long-term culture positivity in CF. A better understanding of A. fumigatus pathogenesis mechanisms in CF is expected to yield insights into when antifungal therapies are warranted. Here, a 4.5-year longitudinal collection of A. fumigatus isolates from a patient with CF identified a persistent lineage that harbors a unique allele of the Pbs2 mitogen-activated protein kinase kinase (MAPKK) necessary for unique CF-relevant stress phenotypes. Importantly for A. fumigatus CF patient diagnostics, this allele provides increased fitness under CF lung-like conditions at a cost of reduced growth under standard laboratory conditions. These data illustrate a molecular mechanism for A. fumigatus CF lung persistence with implications for diagnostics and antifungal therapy.
烟曲霉定植在囊性纤维化 (CF) 个体中以及随后在肺部持续存在的流行率日益受到关注。然而，由于对烟曲霉 CF 发病机制和毒力机制的不确定性，对于 CF 个体中烟曲霉的临床管理尚没有共识。为了填补这一知识空白，对一名 CF 患者进行了一项为期 4.5 年的烟曲霉纵向系列分离物的收集。通过全基因组测序来定义分离株基因型，结果显示肺部存在短暂和持续的烟曲霉。在低氧培养环境中，最容易生长的是持续性谱系分离株，其孢子对氧化应激诱导条件的敏感性高于非持续性分离株。密切相关的持续性分离株携带高渗甘油 (HOG) 途径丝裂原激活蛋白激酶激酶 Pbs2 的独特等位基因 ()。数据表明，该新型等位基因的出现是真菌对低氧环境中渗透胁迫反应所必需的，通过 HOG (SakA) 信号通路的超激活来实现。通过 导致 HOG 途径的超激活，代价是在大气氧水平存在的情况下降低孢子的应激抗性。这些新发现揭示了 CF 中烟曲霉的病理适应机制，为鉴定可能需要抗真菌治疗的持续性烟曲霉分离株奠定了基础，并强调了成功培养持续性 Aspergillus CF 分离株的注意事项。烟曲霉菌感染引起一系列临床表现。对于囊性纤维化 (CF) 患者，过敏性支气管肺曲霉病 (ABPA) 是一种已确立的并发症，但人们越来越认识到在 CF 疾病进展中烟曲霉气道持续存在。目前，对于 CF 中烟曲霉长期培养阳性的临床管理几乎没有共识。更好地了解 CF 中烟曲霉发病机制有望深入了解何时需要抗真菌治疗。在这里，对一名 CF 患者进行了一项为期 4.5 年的烟曲霉纵向分离物收集，鉴定出一个持续性谱系，该谱系携带 Pbs2 丝裂原激活蛋白激酶激酶 (MAPKK) 的独特等位基因，该基因是 CF 相关应激表型所必需的。对烟曲霉 CF 患者的诊断很重要的是，该等位基因在 CF 样肺部条件下提供了更高的适应性，但代价是在标准实验室条件下生长减少。这些数据说明了烟曲霉 CF 肺部持续存在的分子机制，对诊断和抗真菌治疗具有重要意义。
